# RKS: MITOCHONDRIAL UNCOUPLING - A Lesser Known Weight Loss Mechanism

 

# RKS: MITOCHONDRIAL UNCOUPLING 

A LESSER KNOWN WEIGHT LOSS MECHANISM

RKS / 2024-2025 / Ser 5 / Blog 5

1st September 2024

DUAL FUNCTIONING OF MITOCHONDRIA

ATP MFG. + THERMOGENESIS

Dear Reader,

Mitochondria are responsible for creating more than 90% of cellular energy which is necessary for the body to sustain life and support growth. Lying free within the body of all cells – except for red blood corpuscles / cells (RBCs) – mitochondria uniquely contain their very own deoxyribonucleic acid (DNA).

The powerhouse not only energizes the muscles and other tissues but also ignites combustion of end-products of carbohydrates (glucose) and lipids (fatty acids) to burn away extra calories. It is but interesting to understand this complex syncing of mitochondrial activity within the human cells.

CELL PARTS

An average person harbours 30 trillion cells in his / her body on an average. Each cell has three main components:

1. CELL MEMBRANE: This outer lining of cell is also referred to as cell wall.
2. CYTOPLASM: This constitutes the main part of the cell and the mitochondrion - the 'powerhouse', is housed here.
3. NUCLEUS: The nucleus is in the centre of the cell and controls all the activities because of its DNA (carries genes) and messenger carriers (mRNA - messenger ribonucleic acid).

The nucleus commands the task but it is the mitochondria that are instrumental in empowering the body cells and tissues to execute the same.

ENERGY SOURCES & ENERGY PRODUCTION

The sources of energy is in the form of calories that are primarily obtainable from carbohydrates (carbs) and fatty acids. The breakdown of these two substrates initiates the conversion of food energy into chemical form i.e. adenosine triphosphate (ATP). 

• The breakdown process (glycolysis) of glucose (carbs) utilizes the enzyme NAD (nicotinamide adenine dinucleotide) and during glycolysis the the NAD gets converted to NADH (reduced NAD by hydrogen atom addition).
• The breakdown process (beta-oxidation) of fatty acids requires FAD (flavin adenine dinucleotide) and during the utilization of fats this enzyme is converted to FADH2 (FAD + 2 hydrogen atoms). 

It is the NADH and FADH2 that enters the mitochondrial energy generating mechanism to manufacture ATP.

MITOCHONDRIA

The mitochondria have an outer mitochondrial membrane as well as an inner mitochondrial membrane (IMM). In between these two membranes there exists a gap referred to as intermembrane space (IMS). The large portion of the mitochondria, which is bordered by the IMM, is called matrix. 

30 ATP molecules are produced from 1 molecule of glucose whilst 129 molecules of ATP are produced from one fatty acid (palmitic acid) molecule. The ATP production occurs because of: 

• 5 enzymes present in the IMM.
• Movement of protons (H+) within the IMS.

Fig: Mitochondrion.

Each day the body produces 5.9*10^25 molecules of ATP and everyday 10 million ATP molecules are utilized per second by every cell. Hence, each ATP molecule needs to be recycled 1,000-1,500 times (9*10^20 molecules per second) daily and an average individual thereby processes 50 kg of ATP daily.

HOW IS ATP PRODUCED?

The meaning of COUPLING is the act of bringing or coming together. In the mitochondria, the coupling refers to the union of the protons moving in the IMS with the enzyme ATPase synthase (also called enzyme Complex V) present in the IMM to enable generating a force that will manufacture ATP. 

Fig: Mitochondrial structure with respect to ATP generation locus.

It is in the IMM there are 5 enzymes involved in the manufacturing of ATP from either glucose or fatty acids.

• Each glucose molecule generates two NADH molecules whilst each fatty acid (palmitic acid) molecule will release seven FADH2 molecules (to break down 1 palmitic acid molecule it has to undergo seven times beta-oxidation and there is one FADH2 released during each such cycle).
• Enzyme Complex I is where the glucose enters and NAD gets converted to NADH during glycolysis.
• Enzyme Complex II is where the beta-oxidation of fatty acids derived FADH2 (from FAD) makes its way into the IMM.
• The H of NADH and FADH2 splits into H+ and electrons (e-) in Complexes I & II enzymes respectively.
• Enzyme Complexes III and IV receive protons which come from Complexes I & II enzymes and transfer to Complex V enzyme.
• Enzyme Complex V is actually a turbine which is rotated by the protons as they enter the enzyme and ATP gets generated whilst the turbine is set into motion.

Gif: ATP production as protons pass through enzyme Complex V in IMM.

For every two electrons that NADH releases inside the enzyme Complex I, a total of 10 protons are pumped into the IMS: Complex I and Complex III enzymes each pump 4 protons, while Complex IV enzyme pumps 2 protons. One FADH2 results in release of 6 protons in the IMS when it enters the enzyme complex II. The protons (H+) momentum across the IMS results in their forward progression and culminating via their entering the ATPase synthase enzyme and rotating the turbine to generate energy. 

Usually the body makes  adenosine diphosphate (ADP) in platelets and stores in muscles and in all mitochondria. As the turbine moves the energy produced is captured by ADP and enables it to convert to ATP.

Translocation of 3-4 protons fuels one ATP generation. Thus, one NADH generates 3 molecules of ATP whilst one FADH2 manufactures 2 molecules of ATP. 

MITOCHONDRIAL UNCOUPLING

The electrons released from NADH and FADH2 pass across the enzyme complexes - COMPLEX I through to COMPLEX V – along the IMM. In this transfer, referred to as Electron Transfer Chain (ETC), the electrons move from a higher to a lower energy level. In the process energy is released which is utilized to push the moving protons onwards from enzyme Complex I through to enzyme Complex V. 

Besides the ETC benefit for facilitating proton movement in ATP generation, the electrons lower membrane potential and makes the IMM leaky. As a result, many of the protons escape IMS into the mitochondrial matrix and this phenomenon is called mitochondrial uncoupling.

TYPES OF MITOCHONDRIAL UNCOUPLING

It has been demonstrated that uncoupling is a normal activity and 30-50% of mitochondrial functioning is indeed leaking of protons. Movement of H+ from IMS to matrix can be:

1. BASAL LEAK: This is unregulated leaking of H+ and is dependent on the presence of a carrier protein in IMM called adenine nucleotide translocase (ANT).
2. INDUCIBLE LEAK: This is regulated entry of H+ into the matrix caused by electrons short-circuiting the ETC. It is regulated by uncoupling proteins (UCP).

UCP-mediated H+ leaking into the matrix is mediated by free radicals and reactive oxygen species (ROS); on the other hand, fatty acids - especially omega-3, constituting the IMM stimulate ANT-facilitated H+ leak. Resveratrol facilitates mitcohondrial uncoupling by increasing availability of UCP2.

UCP SUBTYPES

1. UCP1: Primarily present in brown adipose tissue (BAT) - predominantly present in shoulder region, backbone area and chest cavity.
2. UCP2: Widely expressed throughout the body.
3. UCP3: Occurs in skeletal muscles and skin.
4. UCP4 & UCP5: Mainly in central nervous system.

PURPOSE OF MITOCHONDRIAL UNCOUPLING

Mitochondria ordinarily transform nutrients to utilizable ATP energy form and this is called mitochondrial respiration. During respiration oxygen is needed but 1-2% of oxygen utilized by mitochondria is converted to free radicals or ROS. The mitochondrial uncoupling is thus responsible for: 

• Limiting ROS production (from enzyme Complexes I & III) by controlling ATP manufacturing. As a result, damage to tissues and aging process of cells (senescence) are checked.
• During cold weather, the mitochondrial uncoupling in BAT by UCP1 burns the contained triglycerides (a type of lipids) to generate heat and thereby minimize shivering.
• Mitochondrial uncoupling increases the combustion process (thermogenesis) so that more heat is generated during mitochondrial respiration. Since the rate of energy expenditure at rest [basal metabolic rate (BMR)] [calculated as BMR (Cal/day = 24 x Body weight (kgs)] accounts for 60% of daily total energy used, H+ leak enhances BMR and results in weight loss. 
• Uncoupling of mitochondria causes ineffective breakdown of nutrients and utilization of calories. The H+ leak results in a situation akin to dietary restriction (DR) and such calorie-deficient diets are now known to increase longevity.
• Exercise increases mitochondrial uncoupling and thereby burns the food calories to generate more heat because of enhanced thermogenesis, rather than allow them to accumulate as stored form of nutrients.

Thus, summarizing, mitochondrial uncoupling has a definite beneficial role to play in terms of limiting cellular senescence and increasing longevity. The interesting outcome of mitochondrial uncoupling is weight loss since the H+ instead of producing ATP promotes thermogenesis or burning of calories – rather than conserving calories! 

INTERMITTENT FASTING

The minimum amount of time it takes to make fasting efficacious hasn't been proven via study, but the prevailing notion is it's somewhere between 12 and 18 hours. The 16/8 popularly adopted method, also called the Leangains protocol, involves an 8-hour eating period and a 16-hour fasting period.

During prolonged intermittent fasting (PF), which is defined as fasting more than 12 hours, there is increased fat breakdown (catabolism) and production of ketones in the liver. It is the ketones that stimulate mitochondrial uncoupling to loose calories in the form of heat which is dissipated.

CONCLUSIONS

Mitochondrial uncoupling is an attractive option for weight loss and promoting a healthy longevity. A omega-3 fatty acids enriched diet increases the expression of mitochondrial UCP3 in muscles resulting in enhance combustion of food calories. Resveratrol, another nutraceutical, enhances UCP2 to promote mitochondrial health. Other foods that promote mitochondrial uncoupling include:

• Cruciferous Vegetables: Cruciferous vegetables such as broccoli, Brussels sprouts, cabbage, cauliflower and kale are rich in nutrients and fiber. They contain compounds that can fuel postbiotics, which aid in mitochondrial uncoupling.

• Other Postbiotic-Boosting Vegetables: In addition to cruciferous vegetables, other veggies like artichokes, asparagus, beets, carrots, garlic, leeks, mushrooms, parsnips and radishes can also boost postbiotics and encourage mitochondrial uncoupling.

• Melatonin-Rich Foods: Melatonin is a hormone that regulates sleep and has antioxidant properties. Foods rich in melatonin, such as pistachios, mushrooms, black rice, olive oil, red wine (in moderation) and strawberries can contribute to mitochondrial uncoupling.

• Leafy Greens: Leafy greens like basil, cilantro, mint, parsley, butter lettuce, romaine, seaweed and spinach are excellent sources of nutrients and can boost mitochondrial uncoupling.

• Fruits That Act Like Fats: Fruits rich in short and long-chain omega-3 and omega-6 fatty acids, such as avocado and olives, support mitochondrial membrane health and promote uncoupling.

• Uncoupling Oils: Oils containing long-chain fatty acids, such as avocado oil, coconut oil, MCT (medium-chain triglycerides) oil, extra virgin olive oil and sesame oil, can optimize mitochondrial function and help promote uncoupling.

• Some Resistant Starches: Resistant starches, which resist digestion and act as fiber in the body, include grain-free bread and wraps made with coconut flour, cassava flour, or almond flour, cassava, green banana, sweet potatoes or yams and yucca. These starches can support mitochondrial uncoupling.

• Nuts and Seeds: Certain nuts and seeds rich in polyamines and polyphenols, such as chestnuts, flaxseeds, macadamia nuts, marcona almonds, pecans, pine nuts and walnuts can help with mitochondrial uncoupling.

• Polyphenol-Rich Fruits: Fruits like blackberries, blueberries, pomegranates and raspberries, which are rich in polyphenols, can promote mitochondrial uncoupling.

• Dairy Products and Replacements: Opt for dairy products from goats, sheep, or A2 beta-casein cows instead of cows that produce A1 beta-casein milk. Examples include aged cheese from Switzerland, buffalo mozzarella, coconut yogurt, goat’s milk cheese, Parmigiano-Reggiano cheese and organic cream cheese. These products contain MCTs and can support ketone production and uncoupling.

Coupling produces energy and uncoupling burns energy. It is but natural that an optimal balance is the most desirable outcome for a healthy mitochondrial functioning. Carbs and fatty acids make mitochondria generate ATP but there are specific foods that will divert mitochondria towards thermogenesis. This is akin to storing what we need but burning what is not needed and is a useless junk.

DR R K SANGHAVI

Prophesied Enabler

Experience & Expertise: Clinician & Healthcare Industry Adviser

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